In collaboration with the Hamza lab at the University of Maryland, we exploited the heme auxotrophy of C. elegans to identify novel factors for heme uptake and trafficking. Using a gene expression microarray-based approach, we identified genes that changed expression in response to changing concentrations of bioavailable heme. We found that two genes, encoding HRG-1 and HRG-4, are essential for heme homeostasis and normal development. We demonstrate that heme deficiency up regulates expression of hrg-1 and its evolutionarily conserved paralog hrg-4. Depletion of either HRG-1 or HRG-4 in worms results in disruption of organismal heme sensing and abnormal response to heme analogs. HRG-1 and HRG-4 are novel transmembrane proteins that bind heme and have evolutionarily conserved functions. Transient knockdown of hrg-1 in zebrafish leads to hydrocephalus, yolk tube malformations, and, most strikingly, profound defects in erythropoiesis - phenotypes that are fully rescued by worm HRG-1.[unreadable] [unreadable] These findings reveal unanticipated and conserved pathways for cellular heme trafficking in animals that define the paradigm for eukaryotic heme transport. Uncovering the mechanisms of heme transport in C. elegans will provide novel insights into human disorders of heme metabolism and generate unique anthelmintics to combat worm infestations.